MDR, XDR, TDR, or XXDR?

Tuberculosis, or TB, an airborne infectious disease, remains one of man’s great adversaries. It is estimated that one third of the world’s population is infected. Although huge strides have been made in reducing the global burden of this disease, a new threat has emerged. Multi and Extensively Drug resistant TB are rewriting the rules.

In 2010, 8.8 million people fell ill with TB and 1.4 million died from it. 95% of these deaths were in the developing world. TB is closely linked with poverty as well as reduced immunity, which is most strikingly seen in the form of increased rates of HIV infection.

Here we examine why drug resistant TB has come into existence, how it can be categorized, what treatment options are available and how the global health community plans to combat this growing threat. We will also look more closely at India, one country particularly bearing the brunt of this emerging challenge.

MDR, XDR, TDR, or XXDR?Drug resistant TB can be divided into 3 categories: Monoresistant, Multi Drug-Resistant (MDR) and Extensively Drug Resistant (XDR) TB. There are currently thought to be 650,000 cases of MDR TB worldwide. Of these, 9% are thought to be XDR cases.

There are 27 MDR TB high burden countries as defined by the WHO (World Health Organisation). Those that bear the highest burdens are India and China. Within these regions 73 from every 1000 cases of TB are thought to be multi drug-resistant. At last count, in 2011, 77 countries worldwide had reported at least one case of XDR TB. In the UK, between 2005 and 2010 there were 16 cases of XDR TB.
In India, reports of Totally Drug Resistant (TDR) TB, or Extremely Drug Resistant TB (XXDR) TB have emerged and present a deadly new threat. In January 2012, there were at least 4 cases of possible TDR TB reported by Hinduja Hospital, Mumbai. The WHO, however, does not yet officially recognise this new resistance category because drug susceptibility testing of second line TB drugs is not yet standardized: what might be resistant in one lab in India could be susceptible elsewhere, and hence the reluctance to use the label definitively.

Therapy and ResistanceFirst Line drugs (FDLs) are classically used for treatment of naïve patients where no TB drug resistance has been found. Alternatively, Second Line Drugs (SDLs) are used once drug resistance is suspected or confirmed.

TB physicians are well versed in the uses of first line drugs to treat TB. The efficacy and side effect profile of second line drugs are much less clear, encompassing a wide a range of classes of drugs including aminoglycosides, polypeptides, fluoroquinolones and thiodamides. There are many others that have sometimes been used in desperation, particularly in XDR TB cases.

Inadequate drug treatment can result in spontaneous genetic mutations in Mycobacterium Tuberculosis (MTB) primarily via the selection of resistant strains. Mutations in one gene, enabling resistance to one drug, might also have a knock-on effect, conferring resistance to other drugs.

Hence, drug resistance can occur where TB drugs are of poor quality, where regimes are unsupervised and not properly completed; or where, quite plainly, the wrong drugs have been given.

In India, first line drugs are available without a prescription. There is availability of second line drugs, but stock regularly runs out at both a central and peripheral level, making the supply erratic. As misuse of first line drugs has been the main cause of rising MDR TB in high burden countries, stewardship of second line drugs is a key priority.